Deletion of a Specific Exon in the Voltage-gated Calcium Channel Gene Disrupts Locomotion in Larvae

TAR DNA-binding protein 43 (TDP-43) is an RNA-binding protein that regulates transcription, translation and alternative splicing of mRNA. We have shown previously that null mutations of the ortholog, (), causes severe locomotion defects in larvae that are mediated by a reduction in the expression of a type II voltage-gated calcium channel, (). We also showed that TDP-43 regulates the inclusion of alternatively spliced exons of ; mutants showed significantly increased expression of isoforms lacking exon 7, a particularly notable finding as only one out of the 15 predicted isoforms lacks exon 7. To investigate the function of exon 7, we generated mutant lines with a deletion that eliminates exon 7. This deletion phenocopies many defects in mutants: a reduction in cacophony protein (Dmca1A) expression, locomotion defects in male and female third instar larvae, disrupted larval motor output, and also reduced activity levels in adult male flies. All these defects were rescued by expression of transcripts containing exon 7. By contrast, expression of a cDNA lacking exon 7 resulted in reduced cacophony protein levels and failed to rescue larval locomotion.